http://www.diva-portal.org
This is the published version of a paper published in Annals of the Rheumatic Diseases.
Citation for the original published paper (version of record):
Andersson, Å., Sardar, S. (2019)
A transcriptional regulator controlling severity in experimental arthritis
Annals of the Rheumatic Diseases, 78(Suppl. 2): 667-667
https://doi.org/10.1136/annrheumdis-2019-eular.7057
Access to the published version may require subscription.
N.B. When citing this work, cite the original published paper.
Permanent link to this version:
FRI0011 A TRANSCRIPTIONAL REGULATOR CONTROLLING SEVERITY OF EXPERIMENTAL ARTHRITIS
Åsa Andersson1,2, Samra Sardar3.1Högskolan i Halmstad, Halmstad University,
Halmstad, Sweden;2Copenhagen, Copenhagen University, Dept of Drug Design
and Pharmacology, Copenhagen, Denmark;3Copenhagen, Nordic Bioscience,
Copenhagen, Denmark
Background: Susceptibility to Rheumatoid Arthritis (RA) is dependent on complex interactions among genetic and environmental factors. Protein candidates and their role in pathways leading to chronic inflammation of the joints, in addition to their potential as drug targets, can be revealed with the help of experimental models for disease (1). From the results of functional genetic studies, we have recently shown that the T-box gene, TBX3, is a candidate gene in Collagen Induced Arthritis (CIA), an experi-mental model for RA (2). TBX3 encodes a transcriptional regulator involved in differentiation of several organs, including bone, during embry-onic development. It has, in addition, been demonstrated important in oncogenesis (3). Our studies suggest that TBX3 has a role in B-cell acti-vation and is important for the severity of disease in the CIA model (2). Objectives: The objective of this project is to understand the role for the transcriptional regulator TBX3 in development of RA.
Methods: Bioinformatics based comparative studies of mouse and human alleles in the regulatory region of TBX3. CRISPR/Cas9-introduced dele-tions and base modificadele-tions in human B-cell lines. Activation of geneti-cally modified B-cells in vitro, followed by analyses of proliferative response and antibody production.
Results: Studies of CIA development in mice with single nucleotide poly-morphisms (SNPs) in the regulatory region of Tbx3 revealed a significant difference in severity of arthritis. In line with this, the anti-collagen type II antibody titers were shown substantially higher in mice with more severe arthritis, even before onset of disease. In addition, preliminary data shows that the proliferative response to Type II collagen upon re-challenge of lymph node cells in vitro is higher in these mice, suggesting a more active response to the disease-inducing antigen. Because the TBX3 gene is conserved between mouse and human, we are investigating whether similar genetic variations are found in the regulatory region of the human TBX3 gene and whether the putative genetic variation would lead to a distinct B-cell phenotype upon activation in vitro.
Conclusion: We suggest that the oncoprotein TBX3 is a novel candidate contributing to disease severity in experimental arthritis. Investigations of genetic variation in the TBX3 gene and its role in the activation of human B-cells will reveal whether this protein is a candidate for influenc-ing also development of RA.
REFERENCES:
[1] Sardar, S and Andersson, Å. Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development. Immunopharmacology and Immunotoxicology. 2016, 38:1.
[2] Sardar, S, et al. The oncoprotein TBX3 is controlling severity in experi-mental arthritis. Arthritis Research and Therapy. 2019, 21:16.
[3] Wilmer, T, et al. The T-Box transcription factor 3 in development and can-cer. 2017, BioScience Trends. 24;11(3).
Disclosure of Interests: Åsa Andersson: None declared, Samra Sardar Employee of: I am a full time employee at Nordic Bioscience
DOI: 10.1136/annrheumdis-2019-eular.7057
FRI0012 THE CLINICAL SPECTRUM AND PEDIGREE ANALYSIS
OF TRAPS IN GREECE, INCLUDING A NOVEL MUTATION-RESULTS FORM A NATIONAL REFERRAL CENTRE
Adrianos Nezos1, Ourania Argyropoulou1, Eleni Klinaki2, Nikolaos Marketos3,
Karagianni Panagiota1, Despoina Maritsi2, Panayiotis Vlachoyiannopoulos1,
Athanasios Tzioufas1.1Medical School, National and Kapodistrian University of
Athens, Department of Pathophysiology, Athens, Greece;2Medical School,
National and Kapodistrian University of Athens, Second Department of Pediatrics, Rheumatology Unit,“P. and A. Kyriakou” Children’s Hospital, Athens, Greece;
3Medical School, National and Kapodistrian University of Athens, Department of
Physiology, Athens, Greece
Background: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) stems from autosomal dominantly inherited mutations in the TNFRSF1A (accession number: NM_001065) gene, encoding for the receptor of tumor necrosis factor a (TNFR1).
Objectives: The aim of the study was to report a novel TNFRSF1A mutation and to describe the clinical phenotypes in families carrying dif-ferent TNFRSF1A mutations.
Methods: Four Greek patients with TRAPS-like clinical features were evaluated for TNFRSF1A gene mutations. Direct sequencing of exons 2, 3 and 4 of the gene was performed. Following positive testing of the index cases, samples from other family members were collected and screened.
Results: A total of eighteen members deriving from four unrelated Greek families were investigated. In the first family, a novel (heterozygous) mutation in cysteine residue in exon 3 of the TNFRSF1A gene C73Y (c.305G>A) was identified in three members. Interestingly, in the same family a patient carrying the low penetrance TNFRSF1A R92Q mutation, as well as a patient with concomitant R92Q and C73Y mutations were identified. In the second family, the TNFRSF1A C73W (c.306C>G) hetero-zygous mutation was identified in seven members. In the third family, the TNFRSF1A T50M mutation was detected in two members while in the fourth family six members carried the TNFRSF1A R92Q mutation in het-erozygous state.
Clinical manifestations amongst members of the affected families were diverse with the most serious being present in patients carrying the TNFRSF1A C73Y, C73W and T50M mutations. Cardinal features included disease onset in childhood (66.7% for C73Y, 85.7% for C73W and 100% for T50M), arthritis (67% for C73Y, 100% for C73W and 100% for T50M), persistent pyrexia (67% for C73Y, 100% for C73W and 100% for T50M), abdominal pain (66.7% for C73Y, 100% for C73W and 100% for T50M), recurrent adhesive ileus (33.3% for C73Y, 14.3% for C73W and 100% for T50M) anterior uveitis (33.3% for C73Y), and diffuse maculo-papular rash (14.3% for C73W and 50% for T50M). The clinical presenta-tion was more severe in the patient with concomitant R92Q and C73Y, suggesting an additive effect. On the contrary, (as expected) the disease spectrum associated with R92Q mutation found in six members encom-passed a mild phenotype, extending from asymptomatic state (four mem-bers) to adult-onset disease associated with intermittent low-grade fever, arthritis and elevated inflammation markers (two members).
Conclusion: This was the first pedigree analysis of TRAPS in Greece, depicting four families with unique mutations, along with analysis of the clinical manifestation. The site of mutation might explain the diversity of clinical phenotypes in TRAPS patients that extends from mild to severe disease. In our patients, it appeared that mutations in the cysteine resi-dues as well as in T50M were associated with more severe clinical man-ifestations. Among these was a novel mutation described for the first time in the literature.
Disclosure of Interests: Adrianos Nezos: None declared, Ourania Argyro-poulou: None declared, Eleni Klinaki: None declared, Nikolaos Marketos: None declared, KARAGIANNI PANAGIOTA: None declared, Despoina Maritsi: None declared, PANAYIOTIS VLACHOYIANNOPOULOS: None declared, Athanasios Tzioufas Grant/research support from: ABBVIE, PFIZER, AMGEN, NOVARTIS, GSK
DOI: 10.1136/annrheumdis-2019-eular.4844
FRI0013 ABSTRACT WITHDRAWN
FRI0014 GENETIC VARIABILITY IN MOLECULES REGULATING
BONE REMODELING. DO THEY INFLUENCE SEVERITY OF DISEASE AND BONE MASS IN PATIENTS WITH EARLY-ONSET ARTHRITIS?
Noelia García Castañeda1, Amalia Lamana1, Nuria Montes1, Ana Ortiz1, Dolores
Martinez-Quintanilla Jimenez1, Cristina Valero1, Pablo Moreno Fresneda1,
Irene Llorente1, Javier Martin Ibanez2, Carmen Martínez3, Rosa P. Gomariz4,
Ana Triguero-Martinez1, Santos Castañeda1, Isidoro González-Álvaro1.1H.U. La
Princesa, IIS-IP, Madrid, Spain;2Instituto de Parasitologia y Biomedicina López-Neyra, CSIC., Granada, Spain;3Facultad Medicina, Universidad Complutense de
Madrid., Madrid, Spain;4Facultad de Ciencias Biológicas, Universidad
Complutense de Madrid, Madrid, Spain
Background: In the last few years, an association has been described between lower bone mass at the onset of disease and higher severity of rheumatoid arthritis (RA).
Objectives: To identify single nucleotide polymorphisms (SNPs) in genes related to bone remodeling associated with severity of disease and bone mineral density (BMD) in patients with early-onset arthritis.
Methods: We included 268 PEARL (Princess Early Arthritis Register Lon-gitudinal) patients genotyped with Ilumina Inc. Immunochip. This array includes 556 SNPs with different density levels in semaphorins 4b, 4d and 4f, DKK1, 2 and 3, sclerostin, osteoprotegerin (OPG), RANK and
